Kinetics of Reactions of Dirhodium and Diruthenium Paddlewheel Tetraacetate Complexes with Nucleophilic Protein Sites: Computational Insights

Abstract

Recently, dirhodium and diruthenium paddlewheel complexes have drawn attention as perspective anticancer drugs. In this study, the kinetics of reaction of typical paddlewheel scaffolds Rh 2 (μ-O 2 CCH 3 ) 4 (H 2 O) 2 , Ru 2 (μ-O 2 CCH 3 ) 4 (H 2 O)Cl, and [Ru 2 (μ-O 2 CCH 3 ) 4 (HO)Cl] − with protein nucleophiles were investigated by means of the density functional theory. The substitution of axial ligands�water and chloride�by the models of protein residue side chains was analyzed, revealing the binding selectivity displayed by these paddlewheel metal scaffolds. The substitution of water is under a thermodynamic control, in which, although the Arg, Cys − , and Sec − residues are the most favorable, their binding is expected to be scarcely selective in a biological context. On the other hand, the replacement of the axial water with a more stable hydroxo ligand induces the chloride substitution in diRu complexes, which also targets Arg, Cys − , and Sec − , although with a moderately higher activation barrier for any examined protein residue. Additionally, the carried out characterization of the geometrical parameters of the transition states permitted determination of the impact of an increased steric hindrance of diRh and diRu complexes on their protein site selectivity. This study corroborates the idea of the substitution of the acetate ligands with biologically active, but more hindering, carboxylate ligands, in order to yield dual acting metallodrugs. This study allows us to assume that the delivery of diRu paddlewheel complexes in their monoanionic form [Ru 2 (μ-O 2 CR) 4 (OH)Cl] − decorated by the bulky substituents R may constitute an approach to augment the selectivity toward anticancer targets, such as TrxR in tumor cells, although under the condition that such a selectivity is operative only in high pH conditions.

Effect of Equatorial Ligand Substitution on the Reactivity with Proteins of Paddlewheel Diruthenium Complexes: Structural Studies

“…The binding to the axial site not only anticipates the later acetate detachment but also could exert a structural destabilization that facilitates its eventual occurrence, as indicated by computational studies. 26 The combination of axial and equatorial coordinative binding has been postulated as a way to establish specific interactions between [Ru 2 Cl 2 (formamidinate) 3 (DMSO)] and ribonucleic acid. 46 ■ ASSOCIATED CONTENT * sı Supporting Information…”

“…Recently, it has been suggested that the use of bulky equatorial substituents on the diruthenium core may constitute an approach to increase the selectivity of diruthenium complexes toward anticancer targets. 26 , 27 Many diruthenium complexes of the type [Ru 2 Cl(L–L) 4 ] (L–L = O,N donors, 28 , 29 N,N′ -donors 30 , 31 or other O,O′ -donors 3 , 32 ) have been synthesized. However, intermediate substitution species [Ru 2 Cl(L–L) x (O 2 CCH 3 ) 4– x ] ( x = 1–3) are quite scarce.…”

“…Recently, it has been suggested that the use of bulky equatorial substituents on the diruthenium core may constitute an approach to increase the selectivity of diruthenium complexes toward anticancer targets. , Many diruthenium complexes of the type [Ru 2 Cl­(L–L) 4 ] (L–L = O,N donors, , N,N′ -donors , or other O,O′ -donors , ) have been synthesized. However, intermediate substitution species [Ru 2 Cl­(L–L) x (O 2 CCH 3 ) 4– x ] ( x = 1–3) are quite scarce. ,− These molecules show variations in the stability, solubility, redox potential, and paramagnetic behavior compared to [Ru 2 Cl­(O 2 CCH 3 ) 4 ] and to their fully substituted species.…”

“…It is possible that the binding of the Asp residues at the equatorial position is a late event in the reaction of paddlewheel complexes with proteins and that the coordination of protein nucleophile sites at the axial position of the bimetallic scaffolds can be an early event in the dimetallic compound/protein recognition process. The binding to the axial site not only anticipates the later acetate detachment but also could exert a structural destabilization that facilitates its eventual occurrence, as indicated by computational studies . The combination of axial and equatorial coordinative binding has been postulated as a way to establish specific interactions between [Ru 2 Cl 2 (formamidinate) 3 (DMSO)] and ribonucleic acid …”

Auranofin Targeting the NDM-1 Beta-Lactamase: Computational Insights into the Electronic Configuration and Quasi-Tetrahedral Coordination of Gold Ions

“…DFT gives a good description of geometries and reaction profiles for complexes formed by transition metals [ 35 , 36 ] and gold in particular [ 37 ]. Therefore, the ωB97X functional is known to reach a high accuracy in the calculation of electronic energies [ 38 , 39 ]. The NBO electron spin densities were calculated as the difference of alpha and beta natural electron configurations [ 40 ].…”